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Many theories have been postulated to explain this remarkable difference in the pediatric and adult population with COVID-19. Here are some of the main theories.

Many theories have been postulated to explain this remarkable difference in the pediatric and adult population with COVID-19.

Role of Angiotensin-Converting Enzyme 2

Like SARS-CoV and coronavirus NL63, recent evidence indicates that entry of SARS-CoV-2 into cells requires the presence of angiotensin-converting enzyme 2 (ACE2) protein. ACE2 receptors are found in cells in the human airway and lungs. Of note, cells expressing little ACE2 were found to be poorly infected with SARS-CoV, while cells expressing more ACE2 were readily infected.

ACE2 is less mature in young children and thus may not function properly as a receptor for SARS-CoV-2. In addition, the intracellular response induced by ACE2 in the alveolar epithelial cells of children may be lower than that of adults.

ACE2 are more abundant on cells of the lower respiratory tract, which is typically the site of severe COVID-19 disease. Consistent with this observation, recent data indicate that children experience more SARS-CoV-2 infections in the upper respiratory tract than the lower respiratory tract.

Foetal Hemoglobin

SARS-CoV-2 virus proteins have been shown to attack the heme on the 1-β chain of hemoglobin to dissociate the iron to form porphyrin. This attack not only reduces hemoglobin leading to hypoxia but also inhibits the normal metabolic pathway of heme. This mechanism moreover interferes with the normal heme anabolic pathway in the human body causing disease.

Newborn infants have up to 80% foetal hemoglobin which may be protective against the coronavirus. However, this explanation does not explain the low incidence of severe disease in older children.

Cross-Immunity with Other Viral Agents

Acquired immunity with other viruses, including other coronaviruses, may be protective to the pediatric population. A study investigating the presence of short-lived relative cross-protection conferred by specific prior viral infections against subsequent respiratory illness showed that adenovirus-positive participants tended to be protected against subsequent infection with adenovirus, coronavirus, enterovirus, rhinovirus, and influenza virus.

On an average, children up to 6 years old can have 8 to 12 Upper Respiratory Tract Infections per year in comparison to adolescents and adults who average 2 to 4 URIs per year. Severity of SARS-CoV-2 infection in infants with more likelihood of hospitalization as compared with toddlers and young children may be explained by the fact that infant’s humoral immunity is initially dependent on maternal immunoglobulins.


 Systemic Inflammatory Response Syndrome

A cytokine storm or systemic inflammatory response syndrome is an overproduction of immune cells and their activating compounds associated with a surge of activated immune cells into the lungs resulting in inflammation and fluid buildup that can lead to respiratory distress and can be contaminated by a secondary bacterial pneumonia. This increases the risk of mortality in patients.

This response is underdeveloped in children and could explain the recently published CDC data where only 54% pediatric cases had cough as compared with 80% in adults. Shortness of breath was also much lower in children compared with adults (13 vs. 43%).

Clinical observations in Wuhan, China, have confirmed that the absolute number of peripheral blood lymphocytes in adult patients progressively declines during the inflammatory response to SARS-CoV-2, which could help the virus to proliferate and spread. The white blood cell count and the absolute number of lymphocytes in pediatric cases were found to be generally normal, which may be related to the incomplete development of natural immunity.

More Efficient T-cells

Day et al. showed that T-cells are especially important in clearing viruses from mice infected with SARS-CoV. Another study in mice also stressed the importance of CD4+ helper T-cells, which stimulate B-cells to make antibodies against pathogens, in controlling SARS-CoV infection. In children, the young immune system and its efficient T-cells may potentially perform a superior job of responding to SARS-CoV-2. T-cell subsets also undergo dynamic changes between younger children and adolescents, particularly with declining T regulatory cells and increasing memory cells.

Asymptomatic but Effective Carriers

The incubation period of COVID-19 has been reported in the range of 0 to 24 days. Studies have shown asymptomatic and presymptomatic carrier transmission of the disease. In the United States, 27% of the pediatric cases that tested positive were asymptomatic. An observational cohort study in Zhejiang, China, reported 28% asymptomatic carriers among exposed children as well. Another study in Shenzhen, China, validated that children are at similar risk of infection as the general population, and less likely to have severe symptoms. These asymptomatic and mildly symptomatic children may play a major role in the spread of SARS-CoV-2 in the community and hence social distancing may be crucial to reduce the rate at which the pandemic spreads across the world. It is recommended limiting a child’s contact with older adults and people with chronic medical conditions.